NEUROPEPTIDE Y ANTAGONISTS AND AGONISTS

Abstract: The invention discloses analogs which behave as NPY antagonists and agonists; and methods of their use for controlling a biological activity such as appetite and cardiovascular function.

Description: NEUROPEPTIDE Y ANTAGONISTS AND AGONISTS Background of the Invention This invention relates to peptide derivatives which are antagonists or agonists of neuropeptide Y. Neuropeptide Y (NPY) , is a 36-residue peptide characterized by a tyrosine (Y) residue at its N-terminus and a tyrosine amide residue at its C-terminus. The peptide was isolated from porcine brain (Tatemoto Proc. Natl . Acad. Sci . U.S.A. 79:5485-5489, 1982) and is considered to be a neurotransmitter or neuromodulator widely distributed in the central and peripheral nervous systems (Allen et al., Neurochem . Int . 8:1-8, 1986). It is the most abundant peptide present in the mammalian brain and heart (Edvinsson et al., Trends Pharmol . Sci . 8:231-235, 1987; Gu et al., Histochem. Cytochem. 32:467- 472, 1984), and is among the most potent vasoconstrictor peptides isolated to date (Lundberg et al., Acta Physiol . Scand. 121:325-332, 1984). However, NPY elicits several physiological responses by activating specific pre- and post-synaptic receptors. Centrally, NPY is thought to be involved in the regulation of food intake, memory processing and circadian rhythm (Sheikh et al., FEBS Lett . 245: 209-214, 1989). In the periphery, NPY seems to function as a transmitter in sympathetic nerves where it interacts with norepinephrine mainly in the regulation of vasculartone (Sheikh et al. FEBS Lett . 245:209-214, 1989) . Different structure-activity relationships for NPY analogs in various model systems have indicated that multiple NPY receptor subtypes exist (Michel, Tips 12:389-394, 1991). ahlestedt and coworkers (Reg l . Pept . 13:307-318, 1986) first suggested the existence of two distinct subtypes of NPY receptors. Post-synaptic (Yl-type) effects could be obtained with the complete NPY molecule, while pre-synaptic (Y2-type) effects were found elicited by long C-terminal fragments, as well as with the entire NPY molecule. Thus, both Yl and Y2 receptors exhibit nearly equal affinity to NPY and its homologous peptide, peptide YY, but only the Y2 receptors could bind to shorter carboxy1-terminal fragments including NPY(13- 36) as described by Sheikh et al. (FEBS Lett . 245:209- 214, 1989). However, since NPY receptors in rat cardiac ventricular membranes discriminate between NPY and peptide YY but bind NPY(13-36), it was suggested that this system be classified as a subtype of Y2 or a new class (designated Y3) of receptors as discussed below (Balasubramaniam et al. Peptides 11:545-550, 1990). NPY is also present in high concentrations in a distinct population of nerve fibers innervating the heart and blood vessels ( harton et al., Ann . N. Y. Acad. Sci . 611:133-144, 1990). NPY is now regarded as the predominant peptide present in the cardiovascular system of mammals. This observation has led to numerous studies of the cardiovascular properties of NPY. For example, several investigations have reported that NPY is a potent vasopressor peptide and that it inhibits the coronary blood flow and contractility in isolated perfused hearts (e.g., see Balasubramaniam et al., Regul . Pept . 21:289- 299, 1988; Allen et al. Regul . Pept . 6:247-253, 1983; Rioux et al. Peptides 7:27-31, 1986) . Furthermore, NPY is also capable of (1) inhibiting the contractile force of isolated cardiac muscles (Balasubramaniam et al. supra) and myocytes (Piper et al. Nuanyn-Scniedberg ' s Arch . Pharmol . 340: 333-337, 1989) and (2) the adenylate cyclase activity and cAMP production by cardiac muscles (Kassis et al., J. Biol. Chem. 262: 3429-3431, 1987) and myocytes (Kassis et al. supra ; Millar et al. Nuanyn- Scniedberg ' s Arch . Pharmol . 338:426-429, 1989), respectively. Specific receptors of NPY in rat cardiac ventricular membranes have been characterized and reported to be more selective to NPY than previously characterized NPY receptors as discussed above (Balasubramaniam et al. Peptides 11:545-550, 1990). The presence of specific receptors of NPY in rat cardiac membranes, the Y-3 receptor, was also reported by visualization with N α biotinyl-NPY analogs (Balasubramaniam et al. Peptides 11: 1151-1155, 1990) . The following table (the abbreviations used are commonly known in the art and are described infra) shows the amino acid homology between NPY and PYY: 5 10 15 20 25 30 35 + + + + + + +. Human NPY YPSKPDNPGEDAPAEDMARYYSALRHYINLITRCIRY Rat NPY YPSKPDNPGEDAPAEDMARYYSALRHYI LITRQRY Rabbit NPY YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY Guinea pig NPY YPSKPDNPGEDAPAEDMARYYSALRHYINUTRQRY Porcine NPY YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY Hunan PYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY Porcine PYY —A S Rat PYY —A S NPY has been implicated in the pathophysiology of a number of diseases including, without limitation, obesity, hypertension and chronic heart failure (CHF) because: (1) hypothalamic NPY levels are elevated in obese rats and decreased in cancer anorectic rats; (2) plasma NPY levels are elevated in CHF and hypertensive patients; (3) negative cardiac inotropic and chronotropic actions; and (4) inhibition of libido and circadian rhythm. Thus, since NPY has been shown to be important for regulating a plurality of physiological events we have set out to design a series of receptor-specific analogs that selectively modulate a variety of biological activities, e.g., appetite and blood pressure activities. Summary of the Invention In general, the invention features analogs which behave as NPY antagonists and agonists. In one aspect, the present invention features compounds having the formula: R 2 - A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -Y-A25-A26-A2 7 _A2 8 _A29_A30-A 31 -A 32 -A 33 - A 34 -A 35 -A 36 - (I) wherein each each R x and R 2 , independently, is H, C 1 -C 12 alkyl (e.g. ,methyl) , C 6 -C 18 aryl (e.g., phenyl), C^-C^ acyl (e.g., formyl, acetyl, and myristoyl) , c 7 ~ c i 8 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylpheny1) ; A 1 is Tyr, or any aromatic amino acid; A 2 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal or Asp; A 3 is Ser, Thr, N-Me-Ser, N-Me-Thr, He, Val, Aib, Anb, Nle, or N-Me-Leu; A 4 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-ε-NH-R (where R is H, a branched or straight chain C^-C^ Q alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 5 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, or D-Trp; A 6 is Gly or is the D- or L- isomer selected from the group consisting of Asp, Glu, N-Me-Asp, Ala, or Aoc; Y is A^A S -A^A^-A^- ^-A^-A^-A^-A^-A^-A 18 - A i9_ A 20_ A 2i_ A 22_ A 23_ A 24 or is absent, where A 7 is Asn, Ala, Gin, Gly, or N-Me-Asn; A 8 is Pro, Ser, Thr, Hyp, D-Ala, N-Me-Ala, Ac 5 c, or D-Pal; A 9 is Gly, N-Me-Gly, Ala, or Trp; A 10 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 11 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 12 is Ala, Nal, Thi , Phe, Bth, Pep, or N-Me-Ala; A 13 is Pro, Hyp , D-Ala , N-Me-Ala , Ac 6 c, D-Pal , Ser , Thr, N-Me-Ser, N-Me-Thr, Ala, Nal , Thi , Phe, Bth, Pep , or N-Me-Ala; A 14 is Ala, Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal Nal , Thi , Phe, Bth, Pep, or N-Me-Ala; A 15 is Glu, Asp, N-Me-Glu, Ala , or Nva; A 16 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 17 is Met, Leu, He, Val , Aib, Anb, Nle, or N-Me-Leu; A 18 is Ala, Asn, Gin, Gly, N-Me-Asn, Nal , Thi , Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl- homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala, A 23 is Ala, Ser, Thr, Nal, Thi, Phe, Bth, Pep, N- Me-Ala, N-Me-Ser, or N-Me-Thr; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^-C^ Q alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-C^ Q alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring (e.g., Me- Trp) ; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring (e.g., Me-Trp) , Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative (e.g., 2-chlorotroptophan, or Tec) ; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-ho o- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^-C^ g alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^-C^ g alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; W is -OH, -N-R 3 R 4 , or OR 5 (where R 3 , R 4 , and R 5 , independently, is H, C^-C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C^-C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl, (e.g., p-methylphenyl) ; wherein, in formula (I) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. Preferably, said pseudopeptide bond is between amino acid residues A 29 -A 30 , A 34 -A 35 , and A 35 -A 36 . Preferred compounds formula (I) include those in which A 32 is D-Trp, D-Phe, D-Tyr, D-Bip, D-Dip, D-Bth, D- Nal, 2-Cl-Trp, Tec, Trp, or a pharmaceutically acceptable salt thereof. In yet other preferred embodiments of the invention the compounds of formula (I) include those in which Y (A 7 -A 24 ) is deleted. Preferably, the compound of formula (I) is [D-Trp 32 ]NPY, cyclo (2/27) Des-AA 7 " 24 [Asp 2 , D-Ala 6 , D-Lys 27 , D-Trp 32 ]NPY, Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY, Des-AA 7"24 [D-Ala 5 , Gly 6 , D-Trp 32 ]NPY or Des-AA 7"24 [D-Trp 5 , Aoc 6 , D-Trp 32 ]NPY . In another aspect, the invention features a compound having the formula: R 2 - X-A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 - (II) wherein X is a chain of 0-7 amino acids, inclusive the N-terminal one of which is bonded to each R 2 and R 2 ; wherein each R x and R 2 , independently, is H, C^-C.^ alk y! ( e -g« methyl), C 6 -C 18 aryl (e.g., phenyl), C^C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 - C 18 alkaryl (e.g., p-methylphenyl) ; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring (e.g., Me- Trp) ; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu, or is deleted; A 31 is He, Cys, D-Ala, Leu, Val, Aib, Anb, N-Me-Ile, or is deleted; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring (e.g., Me-Trp) , Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative (e.g., 2-chlorotroptophan, or Tec) ; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; W is -OH, -N-R 3 R , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C^C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C 1 -C 12 acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 - C 18 alkaryl (e.g., p-methylphenyl) ; wherein, in formula (II) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. Preferred compounds of formula (II) include those where X is A 20 -A 21 -A 22 -A 23 -A 2 -A 25 -A 26 where A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, or N-Me-Thr; A 23 is Ala, Ser, Thr, Nal, Thi, Phe, Bth, Pep, N- Me-Ala, N-Me-Ser, or N-Me-Thr; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo- Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C 2 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C^-C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 alkaryl; or a pharmaceutically acceptable salt thereof. Preferably, said pseudopeptide bond is between amino acid residues A 29 -A 30 , A 34 -A 35 , and A 35 -A 36 . Preferably, the compound of formula (II) is [D- Trp 28 , D-Trp 32 ]NPY (27-36), (Des-Asn 29 [D-Trp 28 , D- Trp 32 ]NPY(27-36) , Des-Asn 29 [D-Trp 28 , D-Trp 32 , Nva 34 ]NPY(27- 36), Des-Asn 29 [Trp 28 , Trp 32 , Nva 34 ]NPY(27-36) , and [D- Trp 28 , Ant 32 , Nva 34 ]NPY(27-36) , Des-Asn 29 [D-Trp 28 , Ant 32 , Nva 3 ]NPY(27-36) , or Des-Asn 29 , Arg 33 [D-Trp 28 , Ant 32 , Nva 34 ]NPY(27-36) . In another aspect the invention features a compound having a formula: / R 2 _ A 25_ A 26_ A 27_ A 28_ A 29_ A 30_ A 31_ A 32_ A 33_ A 34_ A 35_ A 36_ W (III) wherein a disulfide bond is between A 7 and A 21 or is absent; wherein each each R λ and R 2 , independently, is H, C^C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C-^C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylpheny1) ; A 1 is Tyr, or any aromatic amino acid; A 2 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal or Asp; A 3 is Ser, Thr, N-Me-Ser, N-Me-Thr, He, Val, Aib, Anb, Nle, or N-Me-Leu, A 4 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 5 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, or D-Trp; A 6 is Gly or is the D- or L- isomer selected from the group consisting of Asp, Glu, N-Me-Asp, Ala, or Aoc; A 7 is Cys, Glu, Asn, Ala, Gin, Gly, or N-Me-Asn; A 8 is Pro, Ser, Thr, Hyp, D-Ala, N-Me-Ala, Ac 6 c, or D- Pal; A 9 is Gly, N-Me-Gly, Ala, or Trp; Y is A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 or is absent, where A 10 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 11 is Asp, Glu, N-Me-Asp , Ala, or Anb; A 12 is Ala , Nal , Thi , Phe , Bth, Pep, or N-Me-Ala; A 13 is Pro, Hyp, D-Ala, N-Me-Ala , Ac 6 c, D-Pal , Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi , Phe, Bth, Pep, or N-Me-Ala Thr; A 14 is Ala, Pro, Hyp, D-Ala, N-Me-Ala , Ac 6 c, D-Pal Nal , Thi , Phe, Bth, Pep, or N-Me-Ala; A 15 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 16 is Asp, Glu, N-Me-Asp, Ala , or Anb; A 17 is Met, Leu, He, Val , Aib, Anb, Nle, or N-Me-Leu; A 18 is , Ala, Asn, Gin, Gly, N-Me-Asn, Nal, Thi , Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- of L- isomer selected from the group consisting of Arg, D-homo-Arg, D-diethy1-homo-Arg, D-Lys-e-NH-R (where R is H, a branched or straight chain C____-C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Cys, Lys, Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala, A 23 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring (e.g., Me- Trp) ; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring (e.g., Me-Trp) , Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative (e.g., 2-chlorotroptophan, or Tec) ; A 33 is the D- or L- isomer is selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C j -C- ^ g alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; is -OH, -N-R 3 R 4 , or OR 5 (where R 3 , R 4 , and R 5 , independently, is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl,), C^-C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl; wherein, in formula (III) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. Preferably, said pseudopeptide bond is between amino acid residues A 29 -A 30 , A 34 -A 35 , and A 35 -A 36 . Preferably the compound of formula (III) is cyclo(7/21), Des AA 10"17 [Cys 7 , Cys 21 , D-Trp 32 ]NPY, or cyclo(7/21), Des AA 10-17 [Glu 7 , Lys 21 , D-Trp 32 ]NPY. In another aspect, the invention features a compound with pseudopeptide bonds having the formula: *ι R < 2, - A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 - A 32_ Λ 33_ Λ 34_ Λ 35_ Λ 36 _ W (IV) wherein each each R x and R 2 , independently, is H, C- j ^C-^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C^C^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g. , p-methylphenyl) ; A 18 is Ala, Asn, Gin, Gly, N-Me-Asn, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C. j _-C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala, A 23 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring (e.g., Me- Trp) ; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring (e.g., Me-Trp) , Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative (e.g., 2-chlorotroptophan, or Tec) ; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C_ j _-C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic acid; is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C^-C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C j -C-^ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 - C 18 alkaryl (e.g., p-methylphenyl) ; wherein, in formula (IV) each bond can represent either a peptide or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. In preferred embodiments, the compound contains a pseudopeptide bond between A 30 and A 31 ; A 31 and A 32 ; or A 32 and A 33 . In another aspect, the invention features a method of suppressing an NPY mediated physiological response in a tissue other than the heart in a subject comprising administering to said subject a compound having the following formula: Ri R 2 - A 18 -A 19 -A 20 -A 1 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 - A 32 -A 33 -A 34 -A 35 -A 36 - W wherein each each R x and R 2 , independently, is H, C^C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C^C^ acyl (e.g., formyl, acetyl, and myristoyl), c 7 " i 8 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylpheny1) ; A 18 is Ala, Asn. Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C- j ^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, or N-Me-Thr; A 23 is Ala, Ser, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, D-homo-Arg, D-diethyl- homo-Arg, D-Lys-e-NH-R (where R is H, a branched or straight chain C- j -C jg alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring (e.g., Me- Trp) ; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring (e.g., Me-Trp) , Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative (e.g., 2-chlorotroptophan, or Tec) ; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic acid; W is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C -C 22 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 - C 18 alkaryl (e.g., p-methylphenyl) ; wherein, each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. Preferably, said pseudopeptide bond is between amino acid residues A 29 -A 30 , A 34 -A 35 , and A 35 -A 36 . or a pharmaceutically acceptable salt thereof. In preferred embodiments, the method suppresses the activity of the NPY (Y-l) receptor or the NPY (Y-2) receptor. In another aspect, the invention features a method of suppressing a NPY(Y-l) receptor mediated physiological response in the hypothalamus of a subject comprising administering to said subject the compound of formula (I). In another aspect, the invention features a method of suppressing the blood pressure of a subject experiencing hypertension which comprises administering to said subject the compound of formula (I) . In another aspect, the invention features a method of suppressing a NPY(Y-3) receptor mediated physiological response in the cardiovascular system of a subject comprising administering to said subject the compound of formula (IV) . In other preferred embodiments, a therapeutically effective amount of a compound of formula (I) , (II) , (III) or (IV) and a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate or lactose, together form a therapeutic composition capable of suppressing an NPY mediated physiological response. This composition can be in the form a pill, tablet, capsule, liquid, or sustained released tablet for oral administration; or a liquid for nasal administration as drops or spray; or a liquid for intravenous, subcutaneous, parenteral, or intraperitoneal administration. Another preferred form for administration biodegradable sustained-release composition for intramuscular administration to a subject in need of the composition. Preferably, the composition includes a lipophilic salt and is suitable for administration in the form of an oil emulsion or dispersion to a subject in need of the composition. In yet another aspect, the invention features methods for suppressing an NPY mediated physiological response in a subject; such methods involve administering one or more of the above mentioned compounds to a subject in a dosage effective to lower blood pressure; to suppress the appetite; to augment the libido; to stimulate cardiovascular function; on to modulate the circadian rhythm. In still another aspect, the invention features methods for stimulating an NPY mediated physiological response in a subject; such methods involve administering one or more of the above mentioned compounds to a subject in a dosage effective to increase blood pressure; to increase the appetite; to augment the libido; or to stimulate cardiovascular function. The symbol A 1 , A 2 , A 3 , and the like; and Tyr, Lys or the like, as found in a peptide sequence herein stands for an amino acid residue, e.g., =N-CH(R)-CO- when it is at the N-terminus, or -NH-CH(R)-CO- when it is at any other position, where R denotes the side chain (or identifying group) of an amino acid or its residue. For example, R is -CH 2 COOH for Asp, R is -H for Gly, R is - CH 2 OH for Ser, R is -CH 3 for Ala and R is -CH 2 CH 2 CH 2 CH 2 NH 2 for Arg. Also, when the amino acid residue is optically active, it is the L-form configuration that is intended unless the D-form is expressly designated. By pseudopeptide bond is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH 2 - NH; or less preferably that of C)-NH is replaced with any Of CH 2 -S, CH 2 -0, CH 2 -CH 2 , CH 2 -CO, or CH 2 -CH 2 . (A pseudopeptide peptide bond is symbolized herein by or "Ψ".) A detailed discussion of the chemistry of pseudopeptide bonds is given in Coy et al. (1988) Tetrahedron 44:835-841. In other embodiments, the compounds of Formulae (I), (II), (HI), or (IV) are cyclic. Preferably, the cyclization is formed by a disulfide or lactam bridge (amide bond) . In this disclosure, the disulfide or amide bond which links two residues in a compound of the invention are formed between the side chain functionalities. That is, between the side-chain carboxyl group of an acidic amino acid residue (e.g.. Asp or Glu) and the side chain amino group of a basic amino acid residue (e.g., Lys or Orn), or between the side chain sulfhydryl groups of two Cys. In all formulae set forth herein, the amide or disulfide bond between two residues are not shown. A compound of this invention is also denoted by another format, e.g. cyclo (2/27) Des- AA 7 - 24 [Asp 2 , D-Ala 6 , D-Lys 27 , D-Trp 32 ] NPY and cyclo(7/21) Des AA 10"17 [Cys 7 , Cys 21 , D-Trp 32 ]NPY. Preferred cyclic compounds of the invention are cyclo (2/27) Des AA 7 ~ 24 [Asp 2 , D-Ala 6 , D-Lys 27 , D-Trp 32 ] NPY and cyclo(7/21) Des AA 10_17 [Cys 7 , Cys 21 , D-Trp 32 ]NPY. In another aspect, the invention features novel dimeric analogs of NPY. The dimer may be formed by either including one compound of Formula I, II, II, or IV and one compound of Formula I, II, III, or IV. In one embodiment, the dimer is formed by utilizing a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each compound. See R. Vavrek and J. Stewart, Peptides: Structure and Function 381-384 (Pierce Chemical Co. 1983) . Examples of suitable dicarboxylic acid linkers are succinic acid, glutamic acid, and phthalic acid. In other embodiments, the dimer is formed by utilizing an amino acid linker capable of binding to a free amine group of one compound and a free carboxylic acid group of the other compound. Preferably, the amino acid linker is a non-α-amino acid. Examples of suitable amino acid linkers are amino-caproic acid and amino-valeric acid. In yet another embodiment, the dimer is formed by disulfide bridge between cysteines located within each compound. See M. Berngtowicz and G. Piatsueda, Peptides: Structure and Function 233-244 (Pierce Chemical Co. 1985); F. Albericio, et al., Peptides 1990 535 (ESCOM 1991) . Preferred dimeric compounds of the invention are Bis(31/31) [Cys 31 , Trp 32 , Nva 34 ]NPY(27-36) , and Bis(31/31) (Cys 31 , Trp 32 , Nva 34 ]NPY(31-36) , As set forth above and for convenience in describing this invention, the conventional and nonconventional abbreviations for the various amino acids are used. They are familiar to those skilled in the art; but for clarity are listed below. All peptide sequences mentioned herein are written according to the usual convention whereby the N-terminal amino acid is on the left and the C-terminal amino acid is on the right. A short line between two amino acid residues indicates a peptide bond. Abbreviations (common) : Trp = W = Tryptophan Tyr = Y = Tyrosine Val = V = Valine Abbreviations (uncommon) : Aoc = (8-aminooctanoic acid: Orn = Ornithine Nal = 2-napthylalanine Thi = 2-thienylalanine Pep = 4-chlorophenylalanine Bth = 3-benzothienyalanine Bip = 4,4'-biphenylalanine Tic = tetrahydroisoquinoline-3-carboxylic acid Aib = aminoisobutyric acid Anb — α-aminonormalbutyric acid Dip = 2,2-diphenylalanine Ac 6 c = 1-aminocyclohexanecarboxylic acid D-Pal = ,3-(3-pyridyl)alanine; Tec = tetrahydrocarbolenecarboxylic acid Nva = norvaline Ant = anthranilic acid Hyp = hydroxyproline Nle = norleucine The compounds of the invention are useful for reducing, suppressing or mitigating the effects of NPY. For example, the compounds of the invention are especially useful in treating any number of illnesses that involve eating disorders, cardiovascular function, alterations in sexual function, as well as disorders of sleep and circadian rhythms (see, e.g., Harrison 's Principles of Internal Medicine , McGraw-Hill Inc., New York, 12th ed.). Specific examples of such disorders, include without limitation, obesity, anorexia, hypertension, hypotension, congestive heart failure. impotence, dyssomnias and rapid time-zone change syndrome. Strategic design of the NPY antagonists, as described herein, allows for the selective antagonism of different classes of NPY receptors, e.g., Y3 cardiac receptors, without adverse interaction with other NPY receptors. The compounds are also useful for stimulating NPY receptor mediated events, e.g., increasing the blood pressure of a subject. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Description of Preferred Embodiments The drawings will first be described. DRAWINGS Fig. 1 shows the comparison of the effects of D- Trp or D-Trp(CHO) substituted NPY analogs (1.0 μM) on the isoproternol stimulated adenylate cyclase activity of rat hypothalmic membranes. Iso, isoproternol. I., [D-Trp 32 ] Trp 32 ]NPY; II, [D-Trp(CHO) 32 ]NPY; III, [D-Trp 34 ]NPY; IV, [D-Trp(CHO) 34 ]NPY; V, [D-Trp 36 ]NPY; VI, [D-Trp(CHO) 36 ]NPY; a=p,0.01 compared to isoproternol; b, not signifcant compared to isoproternol. Fig. 2 shows the displacement of 125 I-NPY bound to rat hypothalamic membranes by increasing concentrations NPY (•) and [D-Trp 32 ] NPY (D) . Fig. 3 shows the dose-response effects of increasing concentrations of [D-Trp 32 ] NPY (D) , NPY alone (•) ; NPY in the presence of 30 (A) and 300 (I) nM doses of [D-Trp 32 ] NPY on the isoproterenol stimulated adenylate cyclase activity of rat hypothalamic membranes. Fig. 4 shows the comparison of the effects of [D- Trp 32 ]NPY (1.0 μM) on the inhibition of isoproterenol stimulated adenylate cyclase activity of rat hypothalamic membranes by NPY (100 nM) and serotonin (100 nM) . a = p < 0.01 compared to isoproterenol; b, not significant compared to isoproterenol . Fig. 5 shows the antagonism of NPY induced feeding in rats by [D-Trp 32 ]NPY. Fig. 6 shows the effects of 1 μM doses of NPY and its analogs [L-Trp 32 ] NPY, [D-Trp 32 (CHO) ] NPY, [D-Nal 32 ] NPY, [D-Hyp 32 ] NPY, [ (3-1-Tyr 27 ) , D-Trp 32 ] NPY, and [ (3-1-Tyr 27 ' 36 ) , D-Trp 32 ] NPY on isoproterenol stimulated adenylate cyclase activity of rat hypothalamic membranes. (iso = isoproterenol); (a - p < 0.005 vs. iso.); (n.s. = not significant) . Fig. 7 shows the effects of increasing concentrations of NPY in the absence (0) and presence (•) of Des-AA 7"2 [D-Ala 5 , Aoc 6 , D-Trp 32 ] NPY (1 μM) on the isoproterenol stimulated cAMP production by SK-N-MC cells. Also shown is the effect of increasing concentrations of Des-AA 7"2 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY (D) on the isoproterenol stimulated cAMP production by SK-N- MC cells. Fig. 8 shows the effects of increasing concentrations of NPY on the blood pressure of anesthetized rats in the absence (0) and presence (•) of 200 nmol/kg of Des-AA 7"24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY. Fig. 9 shows the effects of increasing concentrations of NPY (o) and NPY (18-36) (Δ) on the binding of 125 I-NPY to SK-N-BE2 cells. Fig. 10 shows the effects of NPY (O) , NPY (18-36) (Δ) and NPY in the presence of lμM dose of NPY (18-36) (•) on forskolin stimulated cAMP production by SK-N-BE2 cells. Figs. 11A-11C show the analytical RPLC of [ψ 30 - 3l ] NPY (18-36) (HA), [ψ 32 - 33 j Npγ (χβ-36) (11B) , and [ψ 33~34 ] NPY (18-36) (HC). Fig. 12 shows the inhibition of 125 I-NPY binding to rat cardiac ventricular membrane by NPY (0) , NPY (18-36) (■) , [ψ 30 / 31 ] NPY (18-36) (Δ) , [ψ 1 / 32 -j NP y (18-36) ( A ), and [ψ 32 / 33 ] N py (is-36) (D) . Any number of analogs of the invention can be synthesized and tested in one or more of the assays are described below or by methods which are known in the art. We now describe preferred embodiments of the invention. STRUCTURE The sequences of naturally occurring NPY are described supra . As is easily observed, there is a high degree of amino acid homology between NPY and PYY. The analogs of the invention have the general formula recited in the Summary of the Invention aJove. The analogs of the invention are based upon the biologically active full-length molecule (amino acids 1- 36) comprising amino acids of NPY and PYY and derivatives thereof; and upon the biologically active subfragments comprising amino acids of NPY and PYY and derivatives thereof. The analogs of the invention may have one or more modifications to the NPY and PYY sequences (see aiove) . For example, the compounds may have one or more of the following modifications which are useful for obtaining selective activity at a NPY receptor: a D-Trp or Aoc or D-Ala in place of one or two or three natural amino acids; or a deletion of several N-terminal amino acids; or the introduction of a pseudopeptide bond instead of a peptide bond between two adjacent amino acids. The analog is capable of acting as a competitive inhibitor of the naturally occurring NPY peptide by binding to the receptor and, by virtue of one of the modifications described supra herein, fail to exhibit the biological activity of the naturally occurring peptide. For example, the peptides for which introduction of a pseudopeptide bond between two residues, or the replacement of one or more natural amino acids with a D- Trp, or the deletion ("des") of the N-terminal residues or internal residues are useful in activity associated NPY activity. The analogs of the invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, or pamoic acid, as wells as polymeric acids and slats with inorganic acids such as the hydrohalic acids, e.g., hydrochloric and sulfuric acids. SYNTHESIS Peptide Synthesis The compounds of the present invention , i.e., compounds of formulas (I) , (II) , (III) , (IV) , and (V) may be synthesized by any techniques that are known to those skilled in the peptide art. Such techniques are described in, e.g.. Solid Phase Peptide Synthesis , eds, John M. Stewart and Janis D. Young, Pierce Chemical Company, Rockford, IL, 2nd edition. The syntheses of the peptides listed in Table 1 and Table 2 were carried out as follows. Peptides were synthesized in an Applied Biosystems model 430A automated instrument, cleaved by hydrogen fluoride, and purified by reversed phase chromatography as described by Balasubramaniam et al. Int . J. Pept . Protein Res . 29:78- 83, 1987; Pept . Res . 1:32-35, 1988). All synthetic peptides were >98% pure as determined by reverse phase chromatography and had the expected amino acid composition and primary structure. Other analogs can be prepared by making appropriate modifications, within the ability of someone of ordinary skill in this field. In addition, pseudopeptide bonds may, if desired, may be introduced at various positions, e.g., between amino acid residues 31-32 of NPY(18-36) or between residues 32-33 of NPY(18-36), or of any peptide as described below. Despite the fact that optically pure Boc-AA-CHO can be obtained in good yields and coupled directly to the α-NH 2 group of the peptide resin by published methods (Sasaki et al., Peptides 8:119-121, 1987; Fehrentz et al.. Synthesis pp.676-678, 1983), this strategy has its limitations because of the possibility of branching at the secondary amine group especially during the synthesis of long peptides with pseudobonds at the C-terminal region. Therefore the utility of several protecting groups, Z, Tos and Z(2-C1), for capping the secondary amine group in the peptide resin was investigated. Although the reaction of the peptide resin with Z-Cl/Tos-Cl (2 equiv.) & DIEA (4 equiv.) completely blocked the secondary amine, the known lability of Z- during repeated acidolysis to remove Boσ group and the apparent resistance of Tos group to HF led us to choose Z(2-Cl) the secondary amine for capping. This is introduced by reacting the peptide resin with Z(2-C1)-0SU (2 equiv.), HOBT (2 equiv.) and DIEA (4 equiv.) for 10-60 min. The red wine color of ninhydrin with secondary amine turned yellow at the end of capping. This method yielded [Ψ 30 / 31 ]NPY(18-36) , [Ψ 31 / 32 ]NPY(18-36) [Ψ 32 / 33 ]NPY(18-36) in greater than 65% yield as judged by analytical HPLC. These peptides not only retained the antagonistic effect, but also exhibited increased affinity (20-220 times) and selectivity for cardiac NPY receptors than NPY(18-36) as discussed below. Integrity of peptides containing pseudobonds were confirmed by mass spectral analysis. Pseudopeptide bond-containing analogs of NPY synthesized by these methods are listed in Table II. Protected amino acid derivatives (Peptide International, Louisville, KY) and peptide synthesis reagents (Applied Biosystems, Foster City, CA) were obtained commercially and used without further purification. Examples of the synthesized analogs are: Formula (I) Compounds [D-Trp 32 ]NPY YPSKPDNPGEDAPAEDLARYYSALRHYINLI [D-Trp] RQRY-NHg [D-Nal 32 ]NPY YPSKPDNPGEDAPAEDLARYYSALRHYINLI [D-Nal]RQRY-N__ 2 [D-Phe 32 ]NPY YPSKPDNPGEDAPAEDLARYYSALRHYINLI [D-Phe]RQRY-NH 2 tD-Hyp 32 ]NPY YPSKPDNPGEDAPAEDLARYYSALRHYINLI [D-Hyp]RQRY-NH 2 [L-Trp 32 ]NPY YPSKPDNPGEDAPAEDLARYYSALRHYI LI [L-Trp]RQRY-NH 2 Des AA 7'24 [D-Trp 32 ] NPY YPSKPD RHYINLI [D-Trp] RQRY-NHj Des AA 7"24 [D-Ala 5 , Aoc 6 ,D-Trp 32 ]NPY YPSK [D-Ala] [Aoc] RHYINLI [D-Trp] RQRY-NH 2 Des AA 7"24 [Aoc 6 , D-Trp 32 ] NPY YPSKP[Aoc] RHYINLI [D-Trp]RQRY-NH 2 Formula (II) Compounds tD-Λla 28 ,D-Trp 32 ]NPY(27-36) Y[D-Ala]NLI [D-Trp] QRY-NH 2 Des-Asn 29 [D-Trp 28 ' 32 ] NPY(27-36) Y[D-Trp]-LI [D-Trp] RQRY-NH 2 Formula (III) Compounds cyclo(7/21), Des AA 10"17 [Cys 7 , Cys 21 , D-Trp 32 ] NPY YPSKPDCPG ARYCSALRHYINLI [D-Trp] RQRY-NH 2 cyclo(7/21), Des AA 10"17 [Glu 7 , Lys 21 , D-Trp 32 ]NPY YPSKPDEPG ARYKSALRHYINLI [D-Trp] RQRY-NH 2 Formula (IV) Compounds [ 3031 ]NPY (18-36) ARYYSALRHYINL ITRQRY-NH j [ 31 32 ]NPY (18-36) ARYYSALRHYINLI TRQRY-NH j [ 32 33 ]NPY (18-36) ARYYSALRHYI LIT RQRY-NH, Other analogs of the invention can be prepared as above and tested for their biological activity effectiveness as antagonists or agonists using the methods described below and those commonly known in the art. FUNCTIONAL ASSAYS Animals, Cell Lines and Cultures, and Reagents Any suitable in vivo or in vitro system may be utilized to assay and test the effectiveness of the compounds of the invention. Such assays may employ in vivo methods for evaluating physiological responses, e.g., blood pressure, renovascular function, feeding behavior, or circadian rhythm, or in vivo biochemical systems evaluating receptor binding in a suitable cell line, e.g., SK-N-MC (ATCC#HBT 10) or SK-N-BE(2) (Barnes et al. In Vitro 17: 619-631, 1981); or in isolated cells, e.g., cells isolated from the spleen, kidney, heart or brain. A number of in vivo and in vitro biochemical systems known to those skilled in the art are available for testing antagonists to NPY receptors, e.g. the Y-l, Y-2, and Y-3 receptor categories. Described below are assay methods which can be utilized with cell lines such as SK-N-MC and SK-N-BE2 or isolated cardiac membranes which possess the high-affinity NPY receptor sites Y-l, Y-2, and Y-3, respectively. Other systems are also known for evaluating NPY antagonists to the Y-l receptor, e.g. VSM cells (Sheikh et al., Am . J. Physiol . 260: G250-G257, 1991) and HEL cells (Motulsky et al. Amer. J. Physiol . 255: E880-E885, 1988); Y-2 receptor, e.g., kidney (Sheikh et al.. Am. J. Physiol 26:F978-F984) , spleen (Lunberg et al., Eur. J. Pharmal. 145:21-29, 1988), dorsal root ganglion (Bleakman et al., Br. J. Pharmal. 103:1781-1789, 1991) and hippocampal cells (Sheikh et al., J. Biol. Chem. 265:8304-8310, 1990); and Y-3 receptors, e.g., in cardiac ventricular membranes (Balasubramaniam et al.. Peptides 11: 545-550, 1990) , chro affin cells, rat gastric mucosa (Michel, M.C., Trends in Pharmol . Sci . 12: 389-394, 1991) and brain stem. In Vitro Biochemical Assays The ability of the compounds of the invention to act as antagonists of NPY can be demonstrated by any number of methods known in the art. For example, the compounds can be shown to compete with iodinated neuropeptide Y for receptors using the methods described by Lundberg et al. (Eur. J. Pharmol . 145: 21-29, 1988); Gordon et al. (J. Neurochemistry 55:506-513, 1990); Walker et al. (Mol . Pharmacol . 34:779-792, 1988); Balasubramaniam et al . (Peptides 10:1283-1286, 1989), and others. In one working example demonstrating antagonists to Y-l receptors, rat hypothalamus was isolated and the membranes were prepared for binding and adenylate cyclase studies according to standard methods (Unden et al. 1984. Eur. J. Biochem 145: 525-530; Westlind-Danielsson et al. 1987. Neurosci . Lett . 74: 237-242). Displacement studies were performed in a total volume of 0.25 ml 20 mM HEPES buffer, pH 7.4, containing 1% bovine serum albumin, 0.1% bacitracin, 300 μm PMSF and 5 KlU/ml aprotinin. In a standard assay, 100 μg of membrane/tube was incubated in a shaking water bath at 24° C for 45 min with [ 125 I-Tyr 1 ]- NPY (20,000 CPM) as described by Balasubramaniam et al (Peptides 11: 545-550, 1990) in the presence of increasing concentrations of NPY (10 -11 -10~ 5 M) . At the end of incubation, 1.0 ml of iced cold buffer was added, centrifuged at 10,000 X g for 10 min, and the supernatant removed by aspiration. The tube containing the pellet was counted for bound radioactivity in a micromedic gamma-counter. An example of assaying adenylate cyclase activity of hypothalamic and cerebral cortex membranes is now described. Adenylate cyclase activity of the hypothalamic and cerebral cortex membranes was determined by incubating 50 μg of membranes in a total volume of 0.20 ml Tris-HCL 30 mM pH 7.4 buffer containing 150 mM NaCl, 8.25 mM MgCl 2 , 0.75 mM EGTA, 1.5 theophylline, 20 μg/ml aprotinin, 100 μg/ml bacitracin, 1 mg/ml bovine serum albumin, 1 mM ATP, 20 mM creatine phosphate, 1 mg/ml phosphocreatine kinase, 10 μM isopreternol, 10 μM GTP, and various concentrations of peptides (0-10 μM) . After incubating the mixture at 35° C for 15 min in a shaking water bath, the reaction was arrested by the addition of 100 μM EDTA and boiling for 3 min. cAMP was extracted and quantitated by radioimmunoassay. All the points in the binding and adenylate cyclase are the means of at least three parallel experiments performed in duplicate. In one working example demonstrating antagonists to Y-3 receptors, rat cardiac ventricular membranes and iodination of NPY were prepared according to the method described by Balasubramaniam et al. (Peptides 11: 545- 550, 1990) . Displacement studies were performed in a total volume of 0.25 ml of 20 mM HEPES assay buffer, pH 7.6, containing 2% bovine serum albumin, 100 μM phenylmethylsulfonyl fluoride, 4 μg/ml leupeptin, 4 μg/ml chymostatin, 5 kallikrein-inactivating units/ml aprotinin, and 0.1% bacitracin. In a standard assay, 200 μg of membrane protein/tube were incubated for 2 h at 18°C in a shaking water bath with 125 I-NPY (40 pM) and increasing concentrations of peptides. At the end of incubation, tubes were vortexed and 150μl aliquots transferred into polypropylene tubes containing 250 μl of ice-cold assay buffer. Unbound 125 I-NPY was separated by centrifugation at 10,000 x g for 10 min followed by aspiration of the supernatant. The tubes containing the pellet were counted for bound radioactivity in a Micromedic γ counter. The IC 50 values were used to calculate the equilibrium dissociation constant, K f° r NPY and NPY antagonists using the equation K L = IC 50 /(1 + F/K d ) , where F and K denote the concentration and the dissociation constant of 125 i-NPY. Adenylate cyclase activity was measured by Rosselin et al. (Biochim . Biophys . Acta 304:541-551, 1977) . Each experiment was carried out in a total volume of 200 μl solution containing 30 mM Tris-HCl, pH 7.4, 150 mM NaCl, 8.25 mM MgCl 2 0.75 mM EGTA, 1.5 mM theophylline, 20 μg/ml aprotinin, 100 μg/ml bacitracin, 1 mg/ml BSA, 1 mM ATP, 20 mM creatine phosphate, 1 mg/ml phosphocreatine kinase, 10 μM isoproterenol, 10 μM GTP, and various concentrations of peptides (0-10 μM) . The reaction was initiated by the addition of 50 μg (50 μl) of membrane protein. After incubation at 35°C for 10 min. in a shaking water bath, the reaction was terminated by the addition of 100 μM EDTA and boiling for 3 min. cAMP was extracted and quantitated by radioimmunoassay using a kit obtained from New England Nuclear, Boston, MA. In Vivo Assays Any suitable m vivo model system can be used to evaluate the antagonistic properties of the compounds of the invention. Such models, without limitation, include those used to evaluate feeding and memory behavior (Flood et al., Peptides 10:963-966), and vasoconstriction and hypertension (Balasubramaniam et al. Biochim et Biophys Acta 997: 176-188, 1989). Thus, in one working example, feeding studies were performed using Spraque Dawley rats (350-450 g) with paraventricular hypothalamic cannulae to investigate effects of NPY analogs (Chance et al. 1989. Peptides 10: 1283-1286) . Antagonism of NPY induced feeding in rats was by [D-Trp 32 ]NPY. Groups of rats received intrahypothalamic injections (l μl) of artificial CSF or 10 μg of [D-Trp 32 ]NPY. Fifteen minutes later CSF-treated rats were injected with CSF (n = 6) , 1 μg of NPY (n = 6) or 10 μg of [D-Trp 32 ]NPY (n = 7) , while the [D-Trp 32 ]NPY- treated rats were injected with 1 μg of NPY (n = 8) . Rats were provided with a known quantity of rat chow, and after 1 hr the food consumed was determined and corrected for spillage a = p < 0.01 vs. CSF; b, not significant vs. CSF; c = p < 0.01 vs. NPY; d = p < 0.05 vs. NPY. In another working example blood pressure studies were performed to evaluate the antagonistic properties of Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY. The method is as follows, after surgical preparation, three doses of NPY (0.1, 1.0 and 10 nmol/kg) were administered by intravenous push to 7 rats in a randomized order. Each dose was separated by a 20 minute washout period. After obtaining baseline systolic blood pressure (SBP) values, the rats received either 200 nmol/kg of Des-AA 7"24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY (n=5) or 0.9% saline (n=2) prior to each NPY dose. Change in SBP from basal state to maximum SBP observed following NPY was compared between baseline and Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY treatments. The duration of SBP effect of Des-AA 7"24 [D-Ala 5 , Aoc 6 , D- Trp 32 ]NPY was determined in 3 animals by administering 1.0 nmol/kg of NPY every 15 minutes for 75 minutes following a single 200 nmol/kg dose of Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D- Trp 32 ]NPY. RESULTS We first synthesized a series of full length analogs of NPY substituting either D-Trp or D-Trp(CHO) in the C-terminal receptor binding region at positions 32, 34 and 36. We tested for agonist activity on isoproterenol-stimulated hypothalamic adenylate cyclase activity. Fig. 1 shows that at 1.0 μM, NPY, [D-Trp 34 ]NPY, [D-Trp 36 ]NPY, and the corresponding formulated D-Trp analogs inhibited isoproterenol-sti ulated hypothalamic adenylate cyclase activity significantly. [D-Trp 32 ]NPY and its formulated derivative, however, did not exhibit significant inhibitory effect on adenylate cyclase activity at this concentration. In the binding experiments shown in Fig. 2, NPY and [D-Trp 32 ]NPY inhibited 125 I-NPY bound to rat hypothalamic membranes in a dose-dependent manner with IC 50 values of 0.63 nM and 3.0 nM, respectively. It is this high receptor activity and the complete loss of intrinsic activity that suggests that [D-Trp 32 ]NPY may be an antagonist of NPY in rat hypothalamus. The complete loss of intrinsic activity, while retaining high binding potency suggested that [D-Trp 32 ]NPY may be an antagonist of NPY in hypothalamus. In order to further substantiate this observation, we investigated the inhibitory effect of NPY on rat hypothalamic membrane adenylate cyclase activity both in the absence and presence of [D-Trp 32 ]NPY. Fig. 3 shows that NPY inhibited isoproterenol stimulated hypothalamic membrane adenylate cyclase activity dose-dependently with an IC 50 value 0.18 nM. [D-Trp 32 ]NPY did not exhibit any inhibitory effect on adenylate cyclase activity. Further, Fig. 3 shows that the presence of 30 and 300 nM [D-Trp 32 ]NPY shifted the inhibitory dose-response curve of NPY on hypothalamic adenylate cyclase activity to the right increasing that IC 50 value to 4.0 nM (K B = 1.41 nM) and 540. nM (K B = 1.36 nM) , respectively. To assess the specificity of [D-Trp 32 ]NPY, we investigated its effect on the inhibitory hypothalamic adenylate cyclase activity of serotonin. Fig. 4 shows that the presence of serotonin (100 nM) significantly (p < 0.01; by repeated measures ANOVA) inhibited the isoproterenol stimulate adenylate cyclase activity both in the absence and presence of [D-Trp 32 ]NPY (1 μM) . The antagonism at [D-Trp 32 ]NPY, therefore, was specific to the NPY receptor since the analog exhibited no effect on the inhibitory hypothalamic AC activity of serotonin and, thus, did not act as a global antagonist. Since hypothalamic NPY has been shown to elicit a feeding response, we also investigated the effect of [D- Trp 32 ]NPY on NPY induced feeding in freely moving rats. Fig. 5 shows that intrahypothalamic injection of NPY (1 μg) significantly (p < 0.01) stimulated the cumulative food intake as compared to vehicle (artificial cerebrospinal fluid) treatment over 1 hr. On the other hand, [D-Trp 32 ]NPY (1 μg) did not stimulate feeding significantly over this period, nor did it attenuate NPY (1 μg) - induced feeding at this concentration. 10 μg of [D-Trp 32 ]NPY also did not exhibit significant effect on feeding, and at this dose significantly (p < 0.05) attenuated the 1 hr. cumulative food intake induced by 1 μg of NPY. All of these observations suggest that D-Trp 32 is a specific and competitive antagonist at NPY in rat hypothalamus in both in vitro and in vivo models. In order to improve the potency and/or selectivity, several analogs were synthesized substituting the residue at 32 with various amino acids, e.g., D-Nal, D-Phe, D-Hyp, or L-Trp (Fig. 6). However, these analogs exhibited agonistic activity which suggests there are strict structural requirements to induce antagonistic properties to NPY. Although it is generally believed that the NPY effects on blood pressure and feeding are mediated by the Y-l receptor subtype, it is possible that NPY analogs which elicit pressor effects have no orexigenic effects. Thus, [D-Trp32]NPY is useful not only to elucidate the receptor subtypes mediating NPY effects on hypothalamus, but also to determine whether feeding and pressor effects are mediated by the Y-l receptors. Next, the relative binding affinities of various compounds having formula (I) were investigated using SK- N-MC (Y-l) and SK-N-BE2(Y-2) shown in Table I. These studies led to the development of two truncated peptide analogs, Des-AA 7"24 [Aoc 6 , D-Trp 32 ]NPY and Des-AA 7 " 24 CD- Ala 5 , Aoc 6 , D-Trp 32 ]NPY, which did not inhibit the cAMP production by SK-N-MC cells (see Table I) . However, Des- AA 7"24 [Aoc 6 , D-Trp 32 ]NPY exhibited poor affinity to Y-l receptors (Table I) , and therefore, failed to antagonize the inhibitory effects of NPY on SK-N-MC cAMP production. On the other hand, Des-AA 7"24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY, surprisingly exhibited moderate affinity (Table I) , and its presence (1.0 μM) shifted the inhibitory dose- response curve of NPY on SK-N-MC cAMP production parallel to the right (Fig. 7) . These observations confirm that Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY is a competitive antagonist of NPY in Y-l receptors. To investigate whether these compounds retained antagonistic activity within an in vivo model, we tested the effects on NPY-induced anorectic rats. Fig. 8 shows that NPY doses of 0.1, 1.0 and 10.0 nmol/kg, during baseline, increased systolic blood pressure (SBP) by 8+7, .26+6 and 37+7 mmHg respectively. Following administration of Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY, NPY doses of 0.1, 1.0 and 10.0 nmol/kg increased SBP by 4+5, 9+5 and 29+17 mmHg respectively. The change in SBP during Des-AA 7-24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY was significantly different than baseline values (p = 0.0002 at the 1.0 nmol/kg NPY doses, but not at the 0.1 or 10 nmol/kg doses. Changes in SBP in control rats receiving saline were not significantly different than baseline values at all NPY doses. The duration of effect of the antagonist ranged between 30-75 minutes. This result demonstrates that Des-AA 7"24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY is effective in attenuating NPY induced vasoconstriction m vivo. Its ability to only affect SBP at the middle NPY dose and the finding that Des-AA 7"24 [D-Ala 5 , Aoc 6 , D- Trp 32 ]NPY can inhibit the binding of 125 I-NPY to SK-N-MC cells, suggests that Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY competitively antagonizes NPY induced hypertension. In addition, further truncation and deletion of Des-AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY resulted in the development of three analogs (Table I) . Although these analogs did not bind to Y-2 receptors, both [D-Ala 28 ], D- Trp 32 ]NPY(27-36) and [Bip 27 , D-Ala 28 , D-Trp 32 ]NPY(27-36) also exhibited poor affinity to Y-l receptor. However, Des-Asn 29 [D-Trp 28 ' 32 ]NPY(27-36) bound with moderate potency to Y-l receptors, and also did not exhibit any intrinsic activity on isoproterenol stimulated cAMP production by SK-N-MC cells. These observations suggest that Des-Asn 29 [D-Trp 28 ' 32 ]NPY(27-36) or its analogs will prove useful for the development low molecular weight selective antagonist compounds for Y-l receptors. TABLE I Peptides IC 50 1 ^) for tne inhibition of 125 I-NPY binding to SK-N-MC SK-N-BE2 (Y-l) (Y- ) NPY 1. 3 0. 1 [D-Trp 32 ]NPY 1000 0. 63 Des-AA 7"24 [Aoc 6 , D-Trp 32 ] NPY 3900 10. 0 Des-AA 7"24 r D-Ala 5 , AOC 6 , D-Trp 32 ] NPY 100 1. 0 [D-Ala 28 , D-Trp 32 ] NPY (27-36) 630 N. I . [Bip 27 . D-Ala 28 , D-Trp 32 ] NPY (27-36) 1300 N. I . Des-Asn 29 [D-Trp 28 ' 32 ]NPY(27-36) 170 N.I. N.I.: no inhibition even at 10,000 nM The analogs of the invention may also be assayed and tested for NPY receptor Y-2 activity using the methods described supra . Thus, a compound, e.g., [D- Trp 32 ]NPY, can be assayed for antagonism using any Y-2 receptor bearing cell, e.g., the SK-N-BE2 cell line, or such cells found in the spleen, kidney, hippocampus or dorsal root ganglion. Towards developing selective agonists and antagonists of Y-2 receptors, we tested a number of compounds using SK-N-BE2 cell lines. These studies demonstrated that NPY(18-36), previously shown to be an antagonist of NPY in rat cardiac membranes bearing Y-3 receptors, antagonizes the inhibitory effect on the cAMP production of SK-N-BE2 cells bearing Y-2 receptor subtypes as shown in Figures 9 and 10. NPY RECEPTOR (Y-3 SUBTYPE) Next, we investigated the effect of introducing a pseudopeptide bond to NPY*18-36) . Table II shows the results for the increased affinity and selectivity of pseudopeptide analogs of NPY(18-36) for Y-3 receptors. The introduction of pseudobonds (-CH 2 NH-) at positions 31-32 or 32-33 of NPY(18-36) was found to substantially increase Y-3 receptor affinity (see Table 2) . Subsequent experiments revealed that all these analogs retain their antagonistic properties. Furthermore, [ψ 30 / 31 ]NPY(18-36) and [ψ 31 / 32 ]NPY(18-36) and [ψ 32 / 33 ]NPY(l8-36) analogs exhibit lower affinity to Y-l and Y-2 subtypes than NPY(18-36) (Table II). Thus, introduction of pseudobonds at 32-33 and 31-32 also increases their selectivity for Y-3 receptors. TABLE II PEPTIDES IC 50 (nM) for the inhibition of 125 I-NPY binding to: Ψ, -CH 2 NH-; N.D., not determined. EXAMPLES This invention is further illustrated by the following nonlimiting examples. EXAMPLE 1 Synthesis of [D-Ala 5 , Aoc 6 , D-Trp 32 ]NPY Peptide Synthesis — MBHA resin (0.45 mM NH 2 group) was placed in a reaction vessel of the Applied Bioscience (ABI) 430A automated instrument and amino acid derivatives were coupled automatically using the standard program provided by the manufacturer modified to incorporate a double coupling procedure. All amino acids were coupled using 2.2 equivalents of preformed symmetrical anhydrides. Arg, Asn and Gin, however, were coupled as preformed 1-HOBT esters (4.4 equal.) to avoid deamidation or lactam formation. At the end of the synthesis N-α-Boc-group was removed and peptide resin (~lg) was treated with HF as described below. In the reaction vessel 1.0 g peptide resin, 0.8 g p-cresol, 0.2g thiocresol, 0.8 ml (CH 3 ) 2 and 5 ml HF were stirred for 40 min of reaction and an additional 60 min. of HF evacuation. During these procedures temperature of reaction vessel was kept between 0°C - 4°C. Then the peptide resin was transferred into a fitted filter funnel in Et 2 0 and washed with excess of Et 2 0. Free peptide was extracted with 30% HOAc (2x15ml) . Peptide solution was diluted to 10% HOAc (60ml H 2 0) and lyophilized. 390 mg crude peptide was obtained from this procedure. EXAMPLE 2 Synthesis of [D-Trp 32 ] NPY Peptide synthesis was performed as described above. Cleavage by HF was as follows: in a reaction vessel l.Og peptide resin, 0.8 ml (CH 3 )C 2 S, 0.8g p-cresol, 0.2g p- thiocreosl and 5ml HF were stirred for 40 min of reaction in temperature between 0°C - " 4°C. After that HF was evacuated in 60. Temperature was still kept below 0°C. The peptide resin was transferred into fitted filter funnel and washed with excess of ET 2 0. The peptide resin extracted with 30ml 30% HOAc. Peptide solution was diluted to 10% HOAc with 60ml H 2 0 and protein lyophilized. Total weight of crude peptide: 190mg. EXAMPLE 3 Synthesis of Cyclo(7/2l), Des-AA 10 " 17 [Cys 7 ' 21 ,D-Trp 32 ] NPY Peptide synthesis was as described above using an Automated ABI 430A synthesizer. The free peptide was obtained by treating the protected peptide resin (l.Og) with HF (10 ml) containing dimethyl sulfide (0.8 ml), p- cresol (0.2g) for 1 h at -2 to -4 C. The residue was transferred to a fitted filter funnel with diethyl ether, washed repeatedly with diethyl ether, and the peptide extracted with 10% HOAC(2X 15 ml) and lyophilized. The crude peptide (lOOmg) thus obtained was dissolved in 6M guanidine HCL (6 ml) diluted with 500 ml of distilled water and the pH adjusted to 8 with ammonia. A solution of potassium ferricyanide (1% w/v) was gradually added with constant stirring until a yellow color persisted. After stirring for an additional 30 min. , the pH of the solution was adjusted to 5 with acetic acid and the solution stirred with an anion exchange resin (AG-3, Cl- form, lOg wet weight) for 30 min, passed through a 0.45 microns filter, and pumped into a semipreparative column (250X10 mm), washed with 0.1%TFA-H 2 0 until a flat base line was obtained. The column containing the peptide was then subjected to gradient elution as described for NPY, and the purified peptide was characterized by amino acid and mass spectral analysis. EXAMPLE 4 Synthesis of Cyclo(7/21), Des-AA 10 " 17 [Glu 7 , Lys 21 , D- Trp 32 ]NPY The synthesis of this peptide was accomplished using the general strategy described for NPY except for the following: After coupling BocGlu(OFM) at position 7, the side chain protecting groups, e-Fmoc group at Lys 21 and the γORm of Glu 7 were removed by removing the peptide resin with 20% piperidine-DMF. After repeated washings with DMF, the e-NH 2 group of Lys 21 was coupled to γ-COOH of Glu 7 by stirring the peptide resin with BOP-HOBT-DIPEA (1:1:3) in DMF (20 ml) overnight, and if cyclization is not complete as judged by the standard ninhydrin test the procedure was repeated until complete cyclization has occurred. The synthesis was then continued in the automated mode, and the free peptide was obtained by the standard HF method described in Example 3. Example 5 Synthesis Of [φ32/33]NPY (18-36) Standard techniques, as described above, were employed for the solid phase synthesis of the carboxy terminal portion of cardiac receptor antagonist, NPY [ψ32/33]NPY (18-36) , up to the point at which introduction of the pseudopeptide bond was desired. The pseudopeptide bond was then introduced in the analog according to the method of Sasaki et al. (Peptides 8:119-121, 1986) , with Boc as the protecting group for the primary amine. The resulting N-α-Boc-peptide-resin with the pseudopeptide bond (0.25 mmol) was swollen in DMF (10 ml) for 10 min in a two-necked R.B. flask fitted with a drying tube. This was followed by the addition of diisopropylethyl amine (1.0 mmol), HOBt (0.5 mmol) and Z(2-C1)0SU (0.5 mmol). HOBt enhances the coupling of Z(2-C1) to the secondary amino group of the pseudopeptide bond. The reaction mixture was stirred at room temperature until the Kaiser's ninhydrin test gave a yellow color indicating that the secondary amine had been blocked. The peptide resin was returned to the reaction vessel of the automated peptide synthesizer and the rest of the sequence was assembled automatically. The free peptide was obtained by the standard cleavage conditions and purified by reverse phase chromatography. USE Because NPY is a potent vasoconstrictor and or orexigenic agent, as well as an inhibitor of libido and effector of circulation rhythm, it is likely that the administration of one or more compounds of the invention may suppress or inhibit the deleterious effects of NPY. Therefore, the NPY antagonists of the invention are suitable for the treatment of any number of diseases related to cardiovascular function (e.g., congestive heart failure or hypertension) , obesity, anorexia, blood pressure, asthma, pulmonary hypertension, renal hypertension, memory retention, sexual dysfunction (e.g. impotence) , and disorders involving sleep and circadian rhythms. For example, the compounds of formula (I) , (II) , (III) are useful for treating for controlling feeding disorders and blood pressure; the compounds of formula (IV) are useful for treating any number of heart ailments, e.g., chronic heart failure, as well as promoting recovery from ischemia since the compounds are expected to enhance myocardium contraction; and the compounds of formula (IV) are useful for controlling NPY actions mediated by Y-2 receptor subtypes, e.g., for controlling the effects of NPY on renal blood flow, glomerular filtration rate, natriuresis and renin secretion. Thus to treat the above disorders, the appropriate NPY antagonist is administered as a therapeutic preparation (as described below) in accordance with the condition to be treated. In the practice of the method of the present invention, an effective amount of an NPY antagonist, e.g., Ψ 30 ~ 31 NPY(18-36) , is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention. These compounds or compositions can thus be administered orally, sublingually, parenterally (e.g., intramuscularly, intravenously, subcutaneously, or intradermally) or by inhalation, and in the form or either solid, liquid or gaseous dosage, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. The dose of the compound of the present invention for treating the above-mentioned disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount". Thus, a typical administration is oral administration or parenteral administration. The daily dose in the case of oral administration is typically in the range of 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration is typically in the range of 0.001 to 50 mg/kg body weight. To be effective for the prevention or treatment of the above-mentioned disorders it is important that the therapeutic agents be relatively non-toxic, non-antigenic and non-irritating at the levels in actual use. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Other embodiments are within the following claims.

Claims: CLAIMS 1. A compound having the formula: *ι R 2 - A 1 -A 2 -A 3 -A -A 5 -A 6 -Y-A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 3 -A 33 - A 34_ A 35_ A 36 _ w (I j wherein each R-L and R 2 , independently, is H, C 1 -C 12 alkyl, c 6 _c i8 Y 1 * c ι" c i2 acy 1 ' C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 1 is Tyr, or any aromatic amino acid; A 2 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal or Asp; A 3 is Ser, Thr, N-Me-Ser, N-Me-Thr,He, Val, Aib, Anb, Nle, or N-Me-Leu; A 4 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arζf, Lys-e-NH-R (where R is H, a branched or straight chain C_ j _-C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 5 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, or D-Trp; A 6 is Gly or is the D- or L- isomer selected from the group consisting of Asp, Glu, N-Me-Asp, Ala, or Aoc; Y is A^A δ -A^A^-A^-A^-A^-A^-A^-A^-A^-A 18 - A 19_ A 20_ A 21_ A 22_ A 23_ A 24 or is a fc, sen t, where A 7 is Asn, Ala, Gin, Gly, or N-Me-Asn; A 8 is Pro, Ser, Thr, Hyp, D-Ala, N-Me-Ala, Ac 6 c, or D-Pal; A 9 is Gly, N-Me-Gly, Ala, or Trp; A 10 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 11 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 12 is Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 13 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, N-Me-Ala, or Thr; A 14 is Ala, Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D- Pal, Nal, Thi, Phe, Bth, Pep, or N-Me- Ala; A 15 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 16 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 17 is Met, Leu, He, Val, Aib, Anb, Nle, or N-Me-Leu; A 18 is Ala, Asn, Gin, Gly, N-Me-Asn, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C-^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 23 is Ala, Ser, Thr, Nal, Thi, Phe, Bth, Pep, N- Me-Ala, N-Me-Ser, or N-Me-Thr; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C-^-C- j ^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer of selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring, Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C_ | _-C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; W is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C^-C-^ alkyl, C 6 -C 18 aryl, C - C 12 acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; wherein, in formula (I) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein Y (A 7 -A 24 ) is absent. 3. The compound of claim 2, wherein said compound has the formula Des AA 7 " 24 , Aoc 6 D-Trp 32 ] NPY. 4. The compound of claim 2, wherein said compound has the formula Des AA 7 " 24 [D-Ala 5 , Aoc 6 , D-Trp 32 ] NPY. 5. A compound having the formula: R l \ R 2 - X-A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 - W (II) wherein X is a chain of 0-7 amino acids, inclusive, the N-terminal one of which is bonded to each R x and R 2 ; wherein each R 2 and R 2 , independently, is each H, C^C- j ^ alkyl, C 6 -C 18 aryl, C^C^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, or N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu, or is deleted; A 31 is He, Cys, D-Ala, Leu, Val, Aib, Anb, or N-Me-Ile, or is deleted; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring. Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-C^ alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; W is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C-L-C^ alkyl, C 6 -C 18 aryl, C^C^ acyl, C 7 -C 18 alkaryl or C 7 -C 18 alkaryl; wherein, in formula (II) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 5, where X is A 20 -A 21 - A 22_ A 23_ A 24_ A 25_ A 26 wnere i n A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr; A 23 is Ala, Ser, Thr, Nal, Thi, Phe, Bth, Pep, N- Me-Ala, N-Me-Ser, or N-Me-Thr; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; W is -OH, -N-R 3 R 4 , or OR 5 (where each R 3 , R 4 , and R 5 , independently, is H, C^C^ alkyl, C 6 -C 18 aryl, C 1 -C 12 acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; or a pharmaceutically acceptable salt thereof. 7. The compound of claim 5 having the formula [D- Ala 28 , D-Trp 32 ]NPY (27-36). 8. The compound of claim 5, having the formula Des-Asn 29 [D-Trp 28 ' 32 ]NPY(27-36) . 9. A compound having the formula: γ - A 18_ A 19_ A 20_ A 21_ A 22_. A 23_ A 24 _ A 25_ A 26-_ A 27_ A 28_ A 29_ A 30_ A 31_ A 32_ A 33_ A 34_ A 35_ A 36_ W (χιI) wherein a disulfide bond is between A 7 and A 21 or is absent; wherein each R-L and R 2 , independently, is H, C^C^ alkyl, C 6 -C 18 aryl, C 1 -C 12 acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 1 is Tyr, or any aromatic amino acid; A 2 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal or Asp; A 3 is Ser, Thr, N-Me-Ser, N-Me-Thr, He, Val, Aib, Anb, Nle, or N-Me-Leu A 4 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 5 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, or D-Trp; A 6 is Gly or is the D- or L- isomer selected from the group consisting of Asp, Glu, N-Me-Asp, Ala, or Aoc; A 7 is Cys, Glu, Asn, Ala, Gin, Gly, or N-Me-Asn; A 8 is Pro, Ser, Thr, Hyp, D-Ala, N-Me-Ala, Ac 6 c, or D- Pal; A 9 is Gly, N-Me-Gly, Ala, or Trp; Y is A 10 -A 1:L -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 or is absent, where A 10 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 11 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 12 is Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 13 is Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, N-Me-Ala, or Thr; A 14 is Ala, Pro, Hyp, D-Ala, N-Me-Ala, Ac 6 c, D-Pal, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 15 is Glu, Asp, N-Me-Glu, Ala, or Nva; A 16 is Asp, Glu, N-Me-Asp, Ala, or Anb; A 17 is Met, Leu, He, Val, Aib, Anb, Nle, or N-Me-Leu; _18 is Ala, Asn, Gin, Gly, N-Me-Asn, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; ,19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Cys, Lys, Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 23 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^-C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring. Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic amino acid; W is -OH, -N-R 3 R 4 , or OR 5 (where R 3 , R 4 , and R 5 , independently, is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C 1 -C 12 acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; wherein, in formula (III) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 3 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 9, having the formula cyclo(7/21), Des AA 10 ~ 17 [Cys 7 , Cys 21 , D-Trp 32 ]NPY. 11. The compound of claim 9, having the formula cyclo(7/21), Des AA 10 " 17 [Glu 7 , Lys 21 , D-Trp 32 ]NPY. 12. A compound with pseudopeptide bonds having the formula: R 2 - A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 - A 32 -A 33 -A 34 -A 35 -A 36 _ w (IV) wherein each ^ and R 2 , independently, is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C^C-^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 18 is Ala, Asn, Gin, Gly, N-Me-Asn, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 19 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethy1-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 20 is Tyr, or any aromatic amino acid; A 21 is Tyr, or any aromatic amino acid; A 22 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala A 23 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Nal, Thi, Phe, Bth, Pep, or N-Me-Ala; A 24 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 25 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C____-C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 26 is the D- or L- isomer selected from the group consisting of His, Thr, 3-Me-His, β- pyrazolylalanine, N-Me-His, Lys, Arg, homo-Arg, diethy1-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 27 is the D- or L- isomer selected from the group consisting of any aromatic amino acid, Lys, or a tethered amino acid with an indole ring; A 28 is Aib or is the D- or L- isomer selected from the group consisting of He, Leu, Val, Anb, Trp, N-Me-Ile, or is deleted; A 29 is Asn, Ala, Gin, Gly, N-Me-Asn, or is deleted; A 30 is Leu, He, Val, Aib, Anb, or N-Me-Leu; A 31 is He, Cys, Leu, Val, Aib, Anb, or N-Me-Ile; A 32 is the D- or L- isomer selected from the group consisting of any aromatic amino acid except L- Tyr, a tethered amino acid with an indole ring, Ant, Ser, N-Me-Ser, Thr, N-Me-Thr, Ala, N-Me-Ala, D-Hyp, or any Trp derivative; A 33 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C.___-C 10 alkyl group, or a C 6 -C 18 aryl group) , Orn, or is deleted; A 34 is Gin, Asn, N-Me-Gln, Nle, Nva, Ala, or Gly; A 35 is the D- or L- isomer selected from the group consisting of Lys, Arg, homo-Arg, diethyl-homo- Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or a C 6 -C 18 aryl group) , or Orn; A 36 is Tyr, or any aromatic acid; W is -OH, -N-R 3 R 4 , or OR 5 (where R 3 , R 4 , and R 5 , independently, is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C x - C 12 acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; wherein, in formula (IV) each bond can represent either a peptide bond or a pseudopeptide bond, provided that said compound cannot contain more than 2 pseudopeptide bonds, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 29 and A 30 . 14. The compound of claim 1, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 30 and A 31 . 15. The compound of claim 1, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 31 and A 32 . 16. The compound of claim 1, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 32 and A 33 . 17. The compound of claim l, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 34 and A 35 . 18. The compound of claim l, 5, 9, or 12, wherein a pseudopeptide bond is positioned between A 35 and A 36 . 19. A dimeric compound comprising one compound from either claims 1, 5, 9, or 12 and one compound from either claims 1, 5, 9, or 12, wherein said dimer is formed by either an amide bond or a disulfide bridge between the two compounds.

Inventors: BALASUBRAMANIAM AMBIKAIPAKAN, BALASUBRAMANIAM, AMBIKAIPAKAN
Applicants: BALASUBRAMANIAM AMBIKAIPAKAN, UNIV CINCINNATI, BALASUBRAMANIAM, AMBIKAIPAKAN, UNIVERSITY OF CINCINNATI
Application year: 1994
Main classification: A61K37
IPC codes: A61K38, A61P3, A61P9, A61P13, A61P15, A61P43, C07K14